RO110491B1 - Taxole derivates preparation process - Google Patents

Abstract

Process for the preparation of a taxol intermediate comprising contacting an alcohol with an oxazinone having the formula: <CHEM> wherein R1 is aryl, heteroaryl, alkyl, alkenyl, alkynyl or OR7 wherein R7 is alkyl, alkenyl, alkynyl, aryl or heteroaryl; R2 and R5 are independently selected from hydrogen, alkyl alkenyl, alkynyl, aryl, heteroaryl, and OR8 wherein R8 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxyl protecting group; and R3 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl.

Description

The present invention relates to a process for preparing taxol derivatives of general formula I:

CORRECTED VERSION - CORRECTED VERSION Reported in: / Reffered to in: BOPI 4 / Ί998

(i) wherein A and B independently represent 10 hydrogen or lower alkanoyloxy, alkenyloxy, alkyloxy or aryloyloxy, or A and B together form an oxcr, L and D independently represent hydrogen or hydroxy or alkanoyloxy, alkenyloxy, 15 lower alkynyloxy or aryloyloxy; E and F independently represent hydrogen, alkanoyloxy, alkenyloxy, lower alkynyloxy or aryloxy, or E and F together form an oxo; G represents hydrogen or hydroxy or alkanoyloxy, alkenyloxy, lower alkynyloxy or aryloyloxy or G and M together form an oxo or methylene or G and M together form an oxirane or M and F together form a 5 oxetane; J represents hydrogen or hydroxy or alkanoyloxy, alkenyloxy, alkyloxy or aryloyloxy or I represents hydrogen, hydroxy or alkyloxy, alkenyloxy, lower alkynyloxy or aryloyloxy or I and J together form an oxo and K represents hydrogen, alkyloxy or alkoxy or , lower alkynyloxy or aryloyloxy and P and Q independently represent hydrogen, alkanoyloxy, alkenyloxy, lower alkynyloxy or aryloxy, or P and Q together form an oxo and S represents hydroxy, and T represents hydrogen and U and V independently represent hydrogen, hydroxy , alkyl, alkenyl, alkynyl, aryl or substituted aryl, heteroaryl and W represent aryl, substituted aryl, heteroaryl, alkyl, alkenyl or alkynyl, alkyloxy, alkenyloxy, alkyne, aryloxy or hetearyloxy.

Of the terpenes, the Texan family of which the taxol is one of the members, has aroused a particular interest in both the field of biology and chemistry.

Taxol is a promising chemotherapeutic agent in the treatment of cancer, with a wide range of antileukemic activity and tumor inhibitor, with the following structure:

Due to this promising activity, taxol is currently used in clinical trials.

The amount of taxol required for these clinical trials is currently obtained from the bark of some 4 5 species of bark. In all cases, the taxol is obtained only in small quantities, from the bark of these slow-growing conifers, producing serious problems in the fact that a limited amount of 50 taxol will not cover the demand for this substance.

A well-known synthetic embodiment refers to the synthesis of the tetracyclic taxane model from available chemicals. Thus, a synthesis of the taxol congener, taxusin, has been made, but the total, final synthesis of taxol is a multi-step, complicated and costly process / JACS 11D, 6558 (1988) '].

Also known is the preparation of taxol which involves the use of a taxol congener, 10 deacetyl baccatin III, which has the structure corresponding to the general formula:

YOUR CORRECT VERSION - CORRECTED VERSION Posted in: / Reffered to in: BOP! 4/1998

1O-Deacetyl baccatin III is more available than taxol, because it can be obtained from the leaves of Taxus baccata (JACS, 110, 5917, (1988)). According to this method, 1O-deacetyl baccatin III is converted to taxol, by attaching 15 to the C-10 acetyl group and by attaching the C-13 β-amide ester side chain, by esterifying the C-13 alcohol with a β-amido carboxylic acid unit. . In fact, this process is carried out in relatively few steps, but the synthesis of the β-amido carboxylic acid unit is a multi-step process, which is carried out with a small amount of product, and the coupling reaction is difficult and, 25 also leads to a small quantity of final product. However, this coupling reaction is an essential step, required in any synthesis of taxol or a taxol derivative, 30 biologically active, being shown that the presence of the β-esteris amido side chain at C-13 is required by antitumor activity, (JACS 93, 2325 (1971)).

A major difficulty, which remains in the synthesis of taxol and other potential antitumor agents, is the lack of an easy-to-use element that can be rapidly attached to C-13 oxygen to produce the ester β-starch side chain. Obtaining such an agent and its binding process under high production conditions would facilitate the synthesis of taxol, as has been shown, with anti-tumor agents having a modified 4 5 set of nuclear substituents or a modified C-13 side chain.

The process according to the invention removes the disadvantages of the known processes, in that, for obtaining 50 compounds of general formula I, an alcohol with an oxazinone of general formula II is subjected to reaction:

aryl; R ₂ and R ₅ are each independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl and 0R _a , wherein R _s represents alkyl, alkenyl, alkynyl, aryl, heteroaryl or a protected hydroxyl group, and R ₃ and R ₆ are each independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; the reaction between alcohol and axazinone being carried out in the presence of an activating agent, in a sufficient amount, with the formation of a β-amidoester, which is an intermediate in the synthesis of the intermediate tissue, which is then converted to taxol.

The process according to the invention has the advantage of obtaining a side-chain pathfinder, for the synthesis of taxoles and the attachment of this side chain precursor, under the conditions of high productivity, in order to obtain a taxol intermediate.

In compounds of general formula II, the aryl meanings represent □ aryl group with 6 ... 15 carbon atoms, alkyl represents an alkyl group with 1 ... 15 carbon atoms, alkenyl represents an alkenyl group with 2 ... 15 atoms. carbon and alkynyl represent an alkynyl group with 2 ... 15 carbon atoms.

Alcohol that reacts with oxazinone has the general formula III:

PhCOO wherein R ₄ is a hydroxyl protecting group, Ph is phenyl and Ac is acetyl or general formula IV:

wherein R ₃ represents aryl, substituted aryl, heteroaryl, alkyl, alkenyl, alkynyl or 0R ₇ , wherein R ₇ represents alkyl, alkenyl, alkynyl, aryl, substituted aryl, or heteroaryl.

wherein A, Β, E, F, G, I, - J, K and M are defined above, and X ₃ and X ₂ are independently hydroxyl protecting groups.

The activating agent is a tertiary amine, selected from triethylamine, diisopropylethylamine, pyridine, N-methylimidazole or 4-dimethylaminopyridine.

In the reaction to obtain compounds of general formula I, an exazinone of general formula Ila is used:

general lla:

wherein R _q represents aryl, heteroaryl, alkyl, alkenyl, alkynyl or 0R ₇ , wherein R ₇ is alkyl, alkenyl, alkynyl, aryl or heteroaryl; R _e is ethoxyethyl hydrogen, 2,2,2-trichlorethoxymethyl or any other hydroxyl protecting group and R ₃ represents aryl, substituted aryl, alkyl, alkenyl or alkynyl. Preferably, in formula II, R _q and R ₃ are phenyl, R ₅ and R ₆ represent hydrogen, and R ₂ is OR _a , wherein R _B is a hydroxyl protecting group.

Thus, 2,4-diphenyl-5- (1-ethoxy-ethoxy) -4,5-dihydro-1,3oxazin-6-one is preferably used with the formula;

The alkyl groups of the taxol, either alone or with different substituents, defined above, are preferably lower alkyl, containing from 1 to 6 carbon atoms in the main chain and up to 10 carbon atoms in the taxol.

These may be straight or branched chains and may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, aryl, hexyl and the like.

The alkenyl groups of the taxol, either alone or with different substituents, defined above, are preferably lower alkenyls, containing from 2 to 6 carbon atoms in the main chain and up to 10 carbon atoms in total. These may be straight or branched chains and may include ethenyl, propenyl, isopropenyl, butenyl, butenyl, isobutenyl, aryl, hexenyl and the like.

The alkynyl groups of the taxol, either alone or together with different substituents, defined above, are preferably lower alkynyl, containing from 2 to 6 carbon atoms in the main chain and up to 10 carbon atoms. These may be straight or branched chains and may include ethynyl, propynyl, butynyl, isobutinyl, aryl, hexynyl and the like.

Alkanoyloxy, taken as an example, contains acetate, propionate, butyrate, valerate, isobutyrate and the like. The most preferred alkanoyloxy is acetate.

The aryl fractions of the taxol, either alone or together with different substituents contain from 6 to 10 carbon atoms and include phenyl, α-naphthyl or β-naphthyl etc; substituents include alkanoxy, hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amide, etc. Phenyl is best suited for aryl.

As presented above, the term aryloxyloxy comprises aromatic heterocyclic moieties, the term aryl includes any compound having an aromatic ring in which there is no hetero atom and the term heteroaryl encompasses any compound having an aromatic ring containing a heteroatom.

Preferred values of substituents A, B, D, L, E, F, G, Μ, I, J,

K, P, Q, S, T, U, V and W are given in the following table.

ι II ω

. - I I II τ ο > II II II ω η Ζ)

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□ XX <Γ cj < with C ω ^s Η £ □ ω CC - ε_ Ο ο ο τ <I II ω II ςζ II II ω η- II II Ζ>

ο

C X S Q> 03 = ω C> 03 τ II Ώ Ν 03 03 L < m II I || Ο II LL '55 - F i Ο ω < LLI □ C ο <- Μ- II

CC ΟΣ □ I Ο . - ω II ω _c I ο α ο I CL I II II II II II II II -> 0. 03 1- Ζ>

> co C ο □ X 03 Ο

CC J3-> 03 Ε Ν ο I <- 03 -ΑτΓ JZ CJ II u_ CL ο σε □ · - Ε the S? ° A II II II ω- c_ H _L Q- CJ < ω -1 £ 111 C9 Σ JE II

CC

a I CC □ And- iS ΣΕ < £ - <|| II ~ 3 II ΣΖ there O II Z II>

0_ II $

ω I <O I o I CJ < I II II II II P II <c m -1 □ IIj LL

WITH T3 C ' CC I m X I I < a The 5l a II A I a I u ¹¹ Λ OS Q. "3 II II IZ II 0_ II a II cn g

> 03 § ° ω § CL ⁼ c> ro t N ^<- 03 m ω I ω- ΣΕ O 2! ^ <£

CJ

I ω

cj ' < II Σ ΣΕ A ω II II LLI LL ω

> 03 > 03 § ° t? x c □ The X E ω c_ a CL ' Π C> 03 , C N E )that N ^<- 03 <- ω a II ~ j ΣΕ * II CD ω ω- £ 1- ω- ω Ε ί- ΣΕ CC II II Ζ> CC II II ΣΖ Q. £ ω Ο Μ-

RO 110491 Bl

The Ac

A

OAc

A

RO 110491 Bl

OAc

A

RO 110491 Bl

RO 110491 Bl

RO 110491 Bl

According to the process of the present invention, oxazines are converted to βamidoesters, in the presence of an alcohol and an activating agent, preferably a tertiary amine such as, for example, 5 triethylamine, diisopropylethylamine, pyridine, N-methylimidazole and 4-dimethylaminopyridine [DM ). For example, oxazinones react with compounds having the tetracyclic taxane nucleus and a hydroxyl group at 10 C-13, in the presence of 4-dimethylaminopyridine (DMAP), to obtain substances having a β-starch group at C-13.

Preferably, the alcohol is 7-0 triethylsilyl baccatin III, which can be obtained according to the method of JACS 110, 5917 (1988) or by other means. Other 10 deacetylbaccatoins III can also be transformed into:

1. (C ₂ H,), SiCl, C, H ₃ N

2. CHjCOCI, CjHjN

a, R = H b, R = COCH ₃

7-0-triethylsilylbaccatin III, according to the reaction scheme above.

Thus, the working conditions being carefully optimized, 10-deacetylbaccatin III is reacted with 20 equivalents of (C _a H ₅ ) ₃ SiCl, at 23 ° C, in a 25 argon atmosphere, for 20 h, in the presence of 50 ml of pyridine / mmol of 10-deacetylbaccatin III, to obtain

7-triethylsilyl-10-deacetylbaccatin III (31a), as a reaction product, with a yield of 30 AcO

7-0-triethylsilylbaccatin III, 31b is reacted with oxazinone 35, according to the present invention, at room temperature to obtain a taxol intermediate product, wherein C-7 and C-2 'hydroxyl groups are protected by 4 0 triethylsilyl and ethoxyethyl, respectively. These groups are then hydrolyzed under conditions that do not disrupt the ester linkages or taxol substituents. The synthesis of taxaz from oxazinone occurs as shown in the reaction scheme above.

As the present scheme refers to the synthesis of the natural taxol product, it can be used, with modifications of 84 ... 86%. after purification.

The reaction product is then acetylated with 5 equivalents of CH ₃ COOCl and 25 ml of pyridine / mmol of 31a, at 0 ° C, in an argon atmosphere, for 48 h, to obtain 86% of 7-0 -threethylsilyl baccatin III (31b) (JACS, 110, 5918 (1988)).

As shown in the following reaction scheme:

oxazinone, as well as tetracyclic alcohol, which may be derived from natural or unnatural sources, for the preparation of other synthetic taxa, according to the present invention.

Alternatively, an oxazinone may be converted to a β-starch, in the presence of a driving agent and an alcohol, other than 7-0-triethylsilyl baccatin III, to obtain a taxol intermediate product. The synthesis of taxol can thus be carried out, using the intermediate compound of taxol, in an appropriate reaction scheme.

Alkyl groups of oxazinone, either alone or with different substituents,

EN 110491 Bl defined above, are preferably lower alkyls, containing 1 ... 6 atoms in the main chain and up to 15 carbon atoms. These can be straight or branched chains and include methyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, aryl, hexyl and the like.

The alkenyl groups of oxazinone, either alone or together with various substituents, presented above, are preferably lower alkenyls, containing from 2 to carbon atoms in the main chain and up to 15 carbon atoms. These may have straight or branched chains and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, aryl, hexenyl and the like.

The alkynyl groups of oxazinone, either alone or with different substituents, described above, are preferably lower alkynyl, containing from 2 to 6 carbon atoms in the main chain and up to 15 carbon atoms; these can be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, aryl, hexynyl and the like.

The alkanoyloxy group of oxazinone comprises acetate, propionate, butionate, valerate, isobutyrate and the like. The most suitable alkanoyloxy is the acetate group.

The arylalkanoyloxy fragments of oxazinone described, either alone or together with different substituents. Contain from 6 to 15 carbon atoms and include phenyl, α-naphthyl or β-naphthyl. Substituents include alkanoxy, hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc. The most suitable aryl group is phenyl.

As shown above, R ₂ and R ₅ of oxazinone of general formula II may be 0R ₈ with r ₈ being alkyl, acyl, ketal, ethoxyethyl (EE), 2,2,2-trichloroethoxymethyl .UT ' ^R 3 ^R e or other hydroxyl protecting groups, such as acetals or ethers, for example methoxymethyl (MOM), benzyloxymethyl; esters, such as acetates, carbonates, such as methyl carbonates and the like.

The chosen hydroxyl protecting group must be easy to remove, under appropriate conditions, so as not to disrupt the ester linkages or other substituents of the intermediate compounds of taxol. In any case, R ₈ is preferably ethoxyethyl or trichloroethoxymethyl and ethoxylethyl.

Preferred values for oxazinone substituents R _1t R ₂ , R ₃ , R ₅ , R ₆ , R ₇ and R ₈ are listed below:

2,2,2specially ale

R ₁ = 0R ₇ R ₄ = Ar R ^ p-MeOPh R ^ alkyl R ^ alkenyl R ^ alkynyl

R _{1 =} H

Rg = ORg

R ₃ = PH R ₃ = Ar R ₃ = p-MeOPh R ₃ = alkyl R ₃ = alkenyl R ₃ = alkynyl

R ₃ = H r ₅ = h R ₆ = H

R ₇ = alkyl R ₇ = alkenyl R ₇ = alkynyl R ₇ = aryl R ₇ = heteroaryl

R _S = EE R _s = alkyl R ₈ = 0C0R R ₈ = M0M R ₈ = CICCH ₂ PCH ₂

As oxazinone II has several asymmetric carbon atoms, the compounds of the present invention may exist in racemic or optically active diastereomeric form. The present invention includes such enantiomers, diastereomers, racemic mixtures and such other mixtures.

Qxazinones II can be prepared according to the following reaction scheme:

It will be prepared according to the following reaction scheme, wherein R-, and R ₃ are phenyl, (32) (33)

Carbonic acid 33 may be prepared by the method described in JACS

110, 5917 (1988). β-Lactam 32 may

RO 110491 Bl

R ₅ and R _s are hydrogen and R ₂ is OR _e with 10 R _a being ethoxyethyl; The reactions take place under the following conditions:

(a) triethylamine, CH ₂ Cl ₂ , 25 ° C, 18 h; [b] 4 equivalents cerium ammonium nitrate, CH ₃ CN, -1O ° C, 10 min; [c] KOH, THF, 15 H ₂ O, = ° C, 30 min; (d) vinyl ethyl ether, THF, toluenesulfonic acid (catalyst), = ° C, 1.5 h; (e) CH ₃ Li, ether, -78 ° C, 10 min; benzoyl chloride, -78 ° C, 1 h.

The initial substances are easily obtained: α-acyloxyacetyl chloride is prepared from glycolic acid and, in the presence of a tertiary amine, it is cyclocondensed with imines, preparations of aldehydes and p-methoxyyaniline, to obtain 1-p. methoxy-phenyl-3-acyloxy-4arilazetidin-2-one.

The p-methoxyphenyl group can be readily removed by oxidation with cerium ammonium nitrate and the acyloxy group can be hydrolyzed under conditions known to obtain 3-hydroxy-4-arylazetidine-2-one.

The 3-hydroxyl group can be protected with various protection groups known as, for example, the 1-ethoxyethyl group. It is preferred that the racemic 3-hydroxy-4-arylazetidine-2-one is dissolved in the pure enantiomers, before protection by recrystallization from the corresponding 2-methoxy-2 esters (trifluoromethylphenylacetic esters and only the dextrogyr enantiomer is used in the preparation.

In any case, 3- (1-ethoxyethoxy) -4-phenylazetidine-2-one can be converted to β-lactam 32, by treatment with a base, preferably 5, / 7-butyllithium and an aroyl chloride, at -78 ° C or lower.

Further examples are given below which illustrate the process according to the invention. 50

Example 1. Preparation of cis-2,4-diphenyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3exazin-6-one 2

1. Cis-1-p-methoxyphenyl-3-acetoxy-4-phenylazetidin-2-one

To a solution of 962 mg (4.56 mmol] of imine derived from benzaldehyde and p-methoxyyaniline and 0.85 ml (6.07 mmol] of triethylamine in 15 ml of CH ₂ Cl ₂ , at -2O ° C, s -dripped 413 mg (3.04 mmol) of α-acetoxyacetyl chloride solution in 15 ml of CH ₂ Cl ₂ .

The reaction mixture is heated to 25 ° C for 18 hours. Then, the reaction mixture is diluted with 100 ml of CH ₂ Cl ₂ and the solution is extracted with 30 ml of 10% aqueous HCl. The organic phase is washed with 30 ml of water and 30 ml of aqueous sodium bicarbonate solution, saturated, dried over sodium sulfate and concentrated to obtain a solid mass. The remaining solid is recrystallized from ethyl acetate / hexane to give 645 mg (68%) of cis1-p-methoxy en yl-3-ketoxy-4-yl lazetide and n-2one, as white crystals. , with a melting point 163 ° C.

2. Cis-3-acetox / -4-phenylazetidin-2-one

To a solution of 20.2 g of c / s-1-β-methoxyphenyl-3-acetoxy-4-phenylazetidin-2-one in 700 ml of acetonitrile at -1O ° C, slowly add a solution of nitrate of Cerium ammonium in 450 ml of water for 1 h. The mixture is stirred for 30 minutes at -10 ° C and diluted with 500 ml of ether. The aqueous phase is extracted with two 100 ml portions of ether and the combined organic phase is washed with two 100 ml portions of water, two 100 ml portions saturated aqueous bisulphite solution.

RO 110491 Sodium bl, two portions of 1OO ml saturated aqueous sodium bicarbonate solution and concentrated to obtain 18.5 g of solid. Recrystallization of the solid from acetone / hexane gives 12.3 g (92%) of c / s-3-acetoxy-4-phenylazetidin-2-one, as white crystals, m.p. 152-154 ° C.

3. Cis-3-hydroxy-4-phenylazetidin-2-one

To a mixture of 200 ml tetrahydrofuran (THF) and 280 ml aqueous 1M potassium hydroxide solution, at □ ° C, add a solution of 4.59 g (22.4 moles) of c / s-3-acetoxy- 4-phenylazetidin-2-one, in 265 ml THF, by a dropper, for 40 min. The solution is stirred at 0 ° C for 1 h and 100 ml of water and 100 ml of saturated aqueous sodium bicarbonate solution are added. The mixture was extracted with 4 portions of 200 ml of ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated to give 3.54 g (97%) of c / s-3-hydroxy-4-phenylazetidine. Racemic -2-wave, in the form of white crystals, with melting point

147 ... 149 ° C.

This compound is again decomposed into its enantiomers by recrystallizing the hexane / acetone 2-methoxy-2 (trifluoromethyl) phenylacetic esters followed by hydrolysis [a] ²⁵ _Hg 177 ° C.

4. Cis-3- (1-ethoxyethoxy) -4-phenylazetidin-2-one

To a solution of 3.41 g (20.9 mmol) of c / s-3-hydroxy-4-phenyl-azetidin-2-one, in 15 ml THF, at 0 ° C, add 5 ml ethyl vinyl ether and 20 mg (0.2 mmol) of sulfonic acid. The mixture is stirred for 20 min, diluted with 20 ml saturated aqueous sodium bicarbonate solution and extracted with 3 portions of 40 ml of ethyl acetate. The combined ethyl acetate phases were dried over sodium sulfate and concentrated to give 4.87 g (99%) of c / s-3- (1-ethoxyethoxy) -4-phenylazetidine-2-one, as colorless oil.

5. Cis-1-benzoyl-3- [1-ethoxyethoxy] -4-phenylazetidin-2-one

To a solution of 2.35 g (10 mmol) of c / s-3- (1-ethoxyethoxy) -4-phenylazetidin-2one, in 40 ml THF, at -78 ° C, is added

6.1 ml (10.07 mmol) of 1.65 M solution of n-butyllithium in hexane. The mixture was stirred for 10 min at -78 ° C, and then a solution of 1.42 g (10.1 mmol) of benzoyl chloride in 10 ml THF was added. This mixture is stirred at -78 ° C for 1 h and diluted with 70 ml of aqueous solution, saturated with sodium bicarbonate and extracted with 3 portions of 50 ml of ethyl acetate. The combined extracts of ethyl acetate are dried over sodium sulfate and concentrated to give 3.45 g of an oily product. Silica gel oil chromatography eluted with ethyl acetate / hexane yields 3.22 g (95%) of cis-1-benzoyl-3- (1-ethoxyethoxy) -4-phenyl-azetidin-2-one, as colorless oil.

6. 2R, 3S-N-benzoyl-O- [1-ethoxyethyl] -3-phenylisoserine

To a solution of 460 mg (1.36 mmol) of c / s-1-benzoyl-3- (1-ethoxyethoxy) 94-phenylazetidine-2-one, in 20 ml THF, at □ ° C, add 13.5 ml 1M aqueous solution (13.5 mmol) potassium hydroxide The mixture is stirred at 0 ° C for 10 min and THF is evaporated, then the mixture is partitioned between 12 ml 1N aqueous HCl solution and 30 ml of chloroform - The aqueous phase is extracted with an additional 2 portions of 30 ml of chloroform. The combined chloroform extracts are dried over sodium sulfate and concentrated to give 416 mg (86%) of 2R, 3S-N-benzoyl. O- (1-ethoxyethyl] -3-phenylisoserine (formula 33, wherein R 1 and R ₃ are phenyl, and R ₂ is ethoxyethyl).

7. Cis-2,4-diphenyl-5- [1-ethoxyethoxy] 4,5-dinitro-1,3-oxazin-6-one 2

To a solution of 416 mg (1.16 mmol) of 2R, 3S-N-benzoyl-O- (1-ethoxyethyl) -

3-phenylisoserine, in 20 ml THF, add 260 mg (2.33 mmol) of solid potassium tert-butoxide, and the mixture is stirred at 25 ° C for 30 min. Then a solution of 134 mg (1.15 mmol) of methanesulfonic acid chloride in 3.2 ml TMF was added and the mixture was stirred at 25 ° C for 1.5 h, then diluted with 80 ml hexane and ethyl acetate, and the same solution is extracted with 20 ml saturated aqueous sodium bicarbonate solution and 10 ml brine. Organic phase

RO 110491 Bl is dried over sodium sulfate and concentrated to give 256 mg (65%) of c / s-2,4-diphenyl-5- (1-ethoxyethoxy) -

4,5-dinitro-1,3-oxazin-6-one 2, as a colorless oil, [α] ²⁵ _Hg -22 ° C (CFCl ₃ , C 5 1.55).

Example 2. Taxol preparation. In a small reaction vessel, 77 mg (0.218 mmol) of (-) - c / s-2,4-diphenyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3-10 oxazine is introduced. -6-one 2, 40 mg (0.057 mmol) of 7-O-triethylsilyl baccatin III, 6.9 mg (0.057 mmol) of 4-dimethylaminopyridine (CPMAP) and 0.029 ml pyridine. The mixture was stirred at 25 ° C for 12 h and diluted with 100 ml of ethyl acetate.

The ethyl acetate solution is extracted with 20 ml aqueous solution of 10% copper sulphide, dried over sodium sulfate and concentrated. The residue was filtered through a silica gel column and eluted with ethyl acetate. Silica gel chromatography, elution with ethyl acetate / hexane, followed by recrystallization from ethyl acetate / hexane afforded 46 mg (77%) of 2'-O- (1-ethoxyethylj-7-O-triethylsilylxaxol with a mixture of about 2: 1 diastereomers and 9.2 mg (23%) of 7-Otrietylsilyl baccatin III. The consumption was quantitative.

A 5 mg sample of 2 '- (1-ethoxyethyl) -7-O-triethylsilylxaxol was dissolved in 2 ml ethanol and 0.5 ml aqueous 0.5% HCl was added. The mixture was stirred at 0 ° C for 30 h and diluted with 50 ml of ethyl acetate. The solution is extracted with 20 ml aqueous sodium bicarbonate solution, saturated, dried over sodium sulfate and concentrated.

The residue is purified on silica gel chromatographic column and eluted with ethyl acetate / hexane and 3.8 mg (90%) of taxol, identical to a sample mixture, is obtained from all points of view.

Example 3. Ndibenzoyl-N-tert-butoxycarbonlatexol preparation

. 2-tert-butoxy-4-phenyl-5- (1-mmol) of N-30 tert-butoxycarbonyl 1-0- (1-ethoxyethyl) -3-phenylisoserine (3) in 20 ml of TMF is added 261 mg (2 , 33 mmol) of solid potassium tert -butoxide, and the mixture is stirred at 25 ° C for 30 min. A solution of 134 mg (1.10 mmol) of methanesulfonic acid chloride in 3.2 ml of TMF is added and the mixture is stirred at 25 ° C for 1.5 h. The mixture is diluted with 80 ml of hexane. and ethyl acetate and this solution is extracted with 20 ml saturated aqueous sodium bicarbonate solution and 10 ml brine.

The organic phase is dried over sodium saulphate and concentrated in 5 to give 235 mg (70%) of 2-tert-butoxy-4-phenyl-5- (1-ethoxyethoxy) -4,5-dihydro-1,3-oxazine- 6-ounce, in the form of colorless oil.

2. N-dibenzooyl-N-tert-butoxycarboniltaxol 50 in a reaction vessel is introduced mg (0.21 8 mmol) of 2-tert-butoxy-4-phenyl-5- (1-ethoxyethoxy) -4,5- dihydro-1,3oxazin-6-one, 40 mg (0.057 mmol) of 7O-triethylsilyl baccatin III, 6.9 mg (0.057 mmol) of 4-dimethylaminopyridine (DMAP) and 0.029 ml of pyridine. The mixture is stirred at 25 ° C for 12 h and diluted with 100 ml of ethyl acetate. The ethyl acetate solution is extracted with 20 ml 10% aqueous solution of copper sulphate, welded over sodium sulfate and concentrated. The residue is filtered through a silica gel column, eluted with ethyl acetate / hexane, followed by recrystallization from ethyl acetate / hexane to give 44 mg (73%) of N-dibenzooyl-N-tert-butoxycarbonyl-2 '- ( 1-ethoxyethoxy) -7-Otrietylsilylxaxol has a mixture of about 1: 1 diastereomers and 9.3 mg (23%) of 7-O-triethylsilyl baccatin III.

A 5 mg sample of N-dibenzooyl-Intert-butoxycarbonyl-2 '- (1-ethoxyethoxy) -7-0-triethylsilylxaxol is dissolved in 2 ml of ethanol and 0.5 ml of solution is added.

RO 110491 Aqueous 0.5% HCl. The mixture is stirred at 0 ° C for 30 h and diluted with 50 ml of ethyl acetate. The solution was extracted with 20 ml saturated aqueous sodium bicarbonate solution, dried over 5 sodium sulphate and concentrated. The residue is purified by column chromatography on silica gel, eluted with

ethyl acetate / hexane and 3.8 mg (about 90%) of N-dibenzooyl-N-tertbutoxycarbonlatexol is obtained.

Example 4. Preparation of Ndibenzoyl-1-tert-butoxycarbonyl-2 '- [1 ethoxyethyl) -3'-phenentaxol

1. 2-Tert-Butoxy-4,4-diphenyl-5- [1-ethoxyethoxy] -4,5-dihydro-1,3-oxazine-6-one

To a solution of 497 mg [1.16 mmol) of N-tert-butoxycarbonyl-0- (1-ethoxyethyl) -3,3-diphenylisoserine (3) in 20 ml of TMF is added 261 mg (2.33 mmol) of a third -butoxies of solid potassium, and the mixture is stirred at 25 ° C for 30 minutes. To the mixture was added a solution of 134 mg (1.16 mmol) of methanesulfonic acid chloride in 3.2 ml THF and stirred at 25 ° C for 1.5 h. The mixture was diluted with 80 ml of hexane and acetate. ethyl and this solution is extracted with 20 ml saturated aqueous sodium bicarbonate solution and 10 ml brine. The organic phase is dried over sodium sulfate and concentrated, to give 243 mg (59%) of 2-tert-butoxy4,4-d -phenyl l-5- (1-ethoxy-ethoxy) -4,5-d ih id ro-1,3oxazin-6-one, as a colorless oil.

2. 90 mg (0.218 mmol) of 2-tert-butoxy-4,4-diphenyl-5- (1-ethoxyethoxy) -4 is introduced into a small reaction vessel. N-dibenzooyl-N-tert-butoxycarbonyl-3'-phenentaxxol , 5-dihydro-1,3-oxazine-6-one, 40 mg [0.057 mmol) of 7-0-triethylsilyl baccatin III, 6.9 mg (0.057 mmol) of 4-dimethylaminopyridine (DMAP) and 0.029 ml of pyridine. The mixture is stirred at 25 ° C for 12 h and diluted with 100 ml of ethyl acetate. The ethyl acetate solution is extracted with 20 ml 10% aqueous copper sulphate solution, dried over sodium sulfate and concentrated. The residue is filtered through a column with silica gel and eluted with ethyl acetate. Silica gel chromatography, elution with ethyl acetate / hexane, followed by recrystallization from ethyl acetate / hexane, yields 44 mg (66%) of N-dibenzooyl-N-tert-butoxycarbonyl-2 '- (1-ethoxyethyl) -3' -phenyl-7-Otrietylsilylxaxol, as a mixture of about 3: 1 diastereomers.

A 5 mg sample of N-dibenzooyl-Intert-butoxycarbonyl-2 '- (1-ethoxyethyl) -3'-phenyl-7O-triethylsilylxaxol is dissolved in 2 ml of ethanol and 0.5 ml of 0.5 aqueous solution is added. % of HCI. The mixture is stirred at 0 ° C for 30 h and diluted with 50 ml of ethyl acetate. The solution is extracted with 20 ml aqueous solution, saturated with sodium bicarbonate, dried over sodium sulfate and concentrated. The residue is purified by column chromatography on silica gel, eluted with ethyl acetate / hexane to give 4.0 mg (about 90%) of Ndibenzoyl-N-tert-butoxycarbonyl-3'-pheniltaxol.

Example 5

Preparation of 2,4-diphenyl-5- [1-ethoxyethoxy] -5-methyl-4,5-dihydro-1,3-oxazineB-one

RO 110491 Bl

CORRECTED VERSION Reported in: / Reffered to in: BOPI 4/1998

To a solution of 430 mg (1.16 10 mmol) of N-benzoyl-O- (1-ethoxyethyl) -2-methyl3-phenylisoserine in 20 ml of THF add 261 mg (2.33 mmol) of potassium tert -butoxide. The mixture is stirred at 25 ° C for 30 minutes. Add a solution of 134 mg (1.16 mmol) of methanesulfonyl chloride in 3.2 ml of THF. The mixture is diluted with 80 ml of hexane and ethyl acetate and this solution is extracted with 20 ml of aqueous solution, saturated, sodium bicarbonate and 10 ml brine The organic phase is dried over sodium sulfate and concentrated to give 270 mg (76%) of 2,4-diphenyl-5- (1-ethoxyethoxy) -5-25 methyl -4,5-dihydro-1,3-oxazine-6-one, as a colorless oil.

Example 6. Preparation of 3'-metiltaxol in a small reaction vessel is 77 mg (0.218 mmol) of 2,4-diphenyl 5- (1-ethoxyethoxy) -5-methyl-4,5-sihydroethylsilyl baccatin III, 6.9 mg (0.057 mmol) of 4-dimethylaminopyridine (DMAP) and 0.029 ml of pyridine.The mixture is stirred at 25 ° C for 12 hours and diluted with 100 ml of ethyl acetate. The solution of ethyl acetate is extracted with 20 ml 10% aqueous solution

wherein A and B independently represent hydrogen or lower alkanoyloxy, alkenyloxy, alkenyloxy or aryloyloxy or A and B together form an oxo; L and D independently represent hydrogen or hydroxy or alkanoyloxy, alkenyloxy, alkyloxy, lower alkylloxy; E and F independently represent hydrogen, alkanoyloxy, alkenyloxy, lower alkynyloxy or aryloxy, or E and F together form an oxo; G represents hydrogen, 50 hydroxy or alkanoyloxy, alkenyloxy, copper sulfate, dried over sodium sulfate and concentrated. The residue is filtered through silica gel and eluted with ethyl acetate. Silica gel chromatography, elution with ethyl acetate / hexane, followed by recrystallization from ethyl acetate / hexane, yields 32 mg (53%) of 2 '- (1-ethoxyethyl] 3'-methyl-7-O-triethylsilylxaxol , as a mixture of about 1: 1 diastereo meri.

A 5 mg sample of 2 '- (1-ethoxyethyl) -3'-methyl-7-O-triethylsilylxaxol is dissolved in 2 ml ethanol and 0.5 ml 0.5% aqueous HCl solution is added. The mixture is stirred at 0 ° C for 30 h and diluted with 50 ml of ethyl acetate. The solution is extracted with 20 ml saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue is purified by column chromatography on silica gel, eluted with ethyl acetate / hexane to give 3.9 mg (about 90%) of 3'-metiltaxol.

Claims (8)

1. Process for the preparation of taxol derivatives of general formula I: (I) lower alkynyloxy or aryloyloxy, G and M together form oxo or methylene or G and M together form oxirane or M and F together form oxetane ; J represents hydrogen, hydroxy or alkanoyloxy, alkenyloxy, lower alkynyloxy or aryloyloxy, or I represents hydrogen, hydroxy or alkanoyloxy, alkenyloxy, alkyloxy or lower aryloxy or I and J together form an oxo and K represents hydrogen, hydroxy RO 110491 Bl CORRECTED VERSION - CORRECTED VERSION Reported in: / Reffered to in: BOPÎ 4/1998 or alkoxy or alkyloxy, alkenyloxy, alkyloxy or lower aryloxy and P and Q independently represent hydrogen or alkanoyloxy, lower alkyloxy or lower alkylyloxy or aryloxy together they form an oxo and S is hydroxy, T is hydrogen and U and V independently represent hydrogen, hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl or substituted aryl, and W is aryl, substituted aryl, heteroaryl, 10 alkyl. alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy or heteroaryloxy, characterized in that an alcohol is reacted with an oxazinone of the formula II: ^R i _'Y ^ x ^{/> 1:15} II <»> ^N X? ^R · Wherein R ₁ represents aryl, substituted aryl, 20 heteroaryl, alkyl, alkenyl, alkynyl or 0R ₇ , wherein R ₇ represents alkyl, alkenyl, alkynyl, aryl or heteroaryl; R ₂ and R ₅ each independently represent radicals selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl and OR _S , wherein R ₈ is alkyl, alkenyl, alkynyl. , heteroaryl aryl or a protected hydroxyl group, and R ₃ and R ₆ are each independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, substituted aryl, or heteroaryl, the reaction between alcohol and oxazinone being made in the presence of an activating agent, in a sufficient amount, with βamidoester formation, which is an intermediate in the synthesis of taxol, an intermediate which is then converted to taxol. Process according to claim 4 0 1, characterized in that the aryl radical is C ₆ aryl. ₁₅ , alkyl is C _1-5 alkyl, alkenyl is C ₂ alkenyl. ₁₅ and alkynyl is C ₂ alkynyl. ₁₅ Process according to claim 4 5 1, characterized in that the alcohol has the general formula III: wherein R ₄ is a hydroxyl protecting group, Ph is phenyl and Ac is acetyl. Process according to claim 1, characterized in that the alcohol has the general formula IV: wherein A, Β, E, F, G, I, J, K and M are defined in claim 1 and X ₁ and X ₂ are independently hydroxyl protecting groups. 5. Process according to claim 1, characterized in that the activating agent is a tertiary amine. 6. Process according to claim 1, characterized in that the activating agent is triethylamine, diisopropylethylamine, pyridine, N-methylimidazole or 4-dimethylaminopyridine. Process according to claim 1, characterized in that oxazinone has the formula Ila: wherein R ₁ represents aryl, substituted aryl, heteroaryl, alkyl, alkenyl, alkynyl or □ R ₇ , wherein R ₇ is alkyl, alkenyl, alkynyl, aryl or heteroaryl; R ₈ represents ethoxyethyl, 2,2,2-trichlorethoxymethyl or any other hydroxyl protecting group and R ₃ represents hydrogen, aryl, substituted aryl, heteroaryl, alkyl, alkenyl or alkynyl. Process according to claim 6, characterized in that, in the general formula Ia of oxazinone, Rt and R ₃ represent phenyl.